NO159169B - ANALOGY PROCESS MEASURES FOR PREPARING DERIVATIVES OF (OKSO-4-4H- (1) -BENZOPYRANE-8-YL) ACETIC ACID WITH ANTITUMORAL THERAPEUTIC ACTIVITY. - Google Patents

Abstract

The invention concerns [oxo-4-4H-[1]-benzopyran-8-yl]-alcanoic acids and their derivatives, their manufacture, represented by the formula. <IMAGE> where AR is hydrogen, a phenyl radical which may or may not be substituted thenyl, furyl, naphthyl, a lower alkyl, cycloalkyl, aralkyl radical; B is a linear or branched lower alkyl radical, either saturated or ethylinically unsaturated; R1 is hydrogen or a phenyl radical; X is hydrogen or a lower alkyl or alkoxy radical and n=1, as well as salts, esters, aminoesters and amides. Compounds and their derivatives may be used as medicines, in particular in the control of tumors.

Description

Procedure for the production of edible water-in-oil emulsions.

The present invention relates to a method for the production of edible water-in-oil emulsions which may possibly have added flavourings, hereditary substances or preservatives, and which are suitable for coating and as an ingredient in foodstuffs.

Up to now, mainly anhydrous fat mixtures have been used for coating foodstuffs or pleasure products, such as confectionery and cakes, which mixtures have the following properties: 1. suitable viscosity (for desired flow properties and uniform coating when dipping as well as desired thickness of the coating); 2. appropriate steel breaking time under manufacturing conditions; 3. desired stuck by the covering at nnmiKie spLsetempera- J turorj 4. uniform appearance without spots;

5. completely continuous oil phase; and

6. ability to be easily released from a mold or a conveyor belt.

However, the production and use of such essentially anhydrous fat-based mixtures creates certain beconomic and physical problems, namely the following: 1. The production of fat-based mixtures requires the use of heavy and expensive mixing and refining equipment which is expensive to maintain and which can be eliminated if an emulsion is used. 2. Changes in product costs due to changes in market prices for fat and sugar can wipe out the usually small profit margins or can make the price of the mixture very unstable. 3. Flavorings in fat-based mixtures can only be tasted if the fat has melted, thereby releasing the flavor particles

from the fat and can act on the taste organs.

4. When coconut is used as a flavouring, it is advisable to cook the coconut to produce a stronger taste per unit weight of the substance, but the water must be removed for the boiled substance

mixed with the fat-based mixture, whereby the benefit of cooking is lost.

5. Inadvertent addition of water to a fat-based mixture for coating applications greatly increases the viscosity of the mixture. 6. Fat-based mixtures produce rather thick layers of fat which tend to peel off when a fat-based product is eaten at temperatures lower than the fat's melting point. Fat-based ice cream toppings are highly brittle and show a tendency to peel, as they are usually eaten at temperatures well below the melting point of the commonly used fats. 7. Any fat-soluble material introduced into a fat-based mixture can only be dispersed in it and tends to make the mixture more viscous. From US Patent No. 3,117,010, certain edible oil-in-water emulsions containing from 30 to 55 percent by weight a<i>v ' "•'a* i in a fat^among liquid vegetable oils and plastic vegetable ; and animal fats, from. 40 to 65 weight percent water, from 1.5 to bj

weight percent of a monoglyceride with an iodine number of at least 40 and from 1 to 7 percent by weight of an emulsifier combination consisting mainly of a lipophilic emulsifier and a hydrophilic one.

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emulsifier, the hydrophilicity/lipophilicity balance of the mono-glyceride and the emulsifier combination being from 5.5 to 11.5 in These emulsions are used in the production of cake and glaze. Although these known oil-in-water emulsions may be useful enough, however, in many cases water-in-oil emulsions, where the oil, and not water, is the continuous phase, will exhibit

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!greater compatibility with many foods with which they are to be used <i>together, and also be better suited for the production of covers that must withstand low temperatures without cracking or peeling off.

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With the help of the invention, a method is now provided for the production of a new, very stable, edible water-in-oil emulsion which is suitable for coating or as an ingredient in foodstuffs, by which method it is mixed together an oil component, water, flavor and color additives and from 1.0 to 12.0 percent by weight, calculated on the oil component, of an emulsifying system consisting of from 0 to 75.0 percent by weight of a non-ionic hydrophilic emulsifier and from 100 to 25 .0 weight percent of a non-I ionic, lipophilic emulsifier, the total hydrophilicity being e-t/. j lipophilicity balance (HLB) a.v the emulsification system is 3 - 6, which-1 method is distinguished by the fact that the oil component is used from. in 1.0 to 10 percent by weight, calculated on this, of a melted, animal or vegetable wax and such an amount of a liquid or melted fat that the total amount of fat, emulsifier, wax! and any oil-soluble or -dispersible flavorings oil. will be from. 4.7 to 98.2 percent by weight calculated on the emulsion, that when a hydrophilic emulsifying agent is used, one with an HLB of at least 7.8 is used, that a lipophilic emulsifying agent with an HLB of hbyst 5 is used, 4 and an iodine value of at least 8, with up to 30% by weight of the lipophilic. emulsifier can be substituted! with a lipophilic diluent with an HLB of at least 5.8 and an iodine number lower than 8, that from 1.8 to 74.0 weight percent water, calculated on the emulsion, and which can contain up to 83 weight percent in sugars and other water-soluble and water-dispersible flavorings j: !o.l., calculated for the emulsion, are heated to the mixture's temperature and <g> are added under sufficiently vigorous stirring so that the mixture's homogeneity is maintained, and that the mixture is whisked until the desired range of droplet sizes of the emulsion's water is achieved. phase. A water-in-oil emulsion produced by the method according to the invention retains all the desirable properties of the fat-based mixtures now used for coating purposes. Against the j;ol je-in-va.nn emulsion ions according to the above-mentioned US patent document no. 3,117,010, the water-in-oil emulsions produced by the frenlj method according to the invention exhibit advantages in many applications j is due to the fact that the oil is the continuous phase, and furthermore j the addition of wax in the present emulsions has a remarkable j

Worthy ability to improve the stability of emulsions. This will be evident from the tests of emulsions with and without wax addition which are described at the end of the description.

In the method according to the invention, the first step consists in mixing liquefied fat or oil together with wax and the emulsification system. An oil can then be added

: suitable flavoring or coloring matter or other optional materials to the mixed oil phase, and the conversion of this is continued until

in the flavoring and coloring matter is dissolved or thoroughly dispersed this'. Then the water, sugar, and any desired water-incompatible optional materials are mixed together, and the aqueous phase is heated to the temperature at which the emulsion is to be prepared; The aqueous phase is then added to the liquefied mixture of fat and emulsifier at such a rate that the homogeneity of the mixture is maintained during stirring. The mixture is then further processed for a sufficiently long time so that the melting range for the droplets of the aqueous phase corresponds to the known values for such emulsions.

The component used in the method according to the invention must, as mentioned, be edible, and preferably there can ! one or more vegetable oils are used which can be fully or partially newly hydrogenated, or a fraction of a hydrogenated vegetable oil or mixtures of such oils. The nature of the oil component determines the melting point of the emulsion and thus;

In the applications for which the emulsion is suitable. The choice of >■ I the oil component thus partially determines the coating of nutrients at a given temperature, the hardness of the coating at different eating temperatures and the flavor and aroma of the coating (together with other flavourings).

The desired sugar is omitted when the present water-in-oil emulsions are used in connection with foodstuffs for humans who must limit sugar consumption, sugar is used in most of the emulsions, and the present method of production $.v jva.nn-in-oil je emulsions must be described for the case where sugar is added. Changes in the ratio of sugar: water or water: fat or fat: sugar or in the nature of the emulsification system. causes changes in the properties of the water-in-oil emulsions or can even cause breaking of the emulsion and the separation, if any, of this in an oil phase and a water phase. In the emulsions produced according to the method according to the invention, two liquid phases are present to carry flavor and/or coloring agents (ie the oil phase I and the water phase) in contrast to what as is the case for a sus- •. pension of solids in one liquid phase in the known fat-based coatings. Water-in-oil emulsions can be prepared with 1. an oil-soluble flavoring agent and an oil-soluble dye<;>

2. a water-soluble flavoring agent and a water-soluble dye! 3. an oil-soluble flavoring agent and a water-soluble coloring agent; 4. and oil-soluble dye and a water-soluble flavoring agent'

j 5. flavoring and coloring matter are dispersible rather than

ij soluble in an oil or water phase. j in-Water*in-oil emulsions thus make it possible to use different coloring and flavoring substances regardless of their solubility.

It has been shown that by varying the materials in the mixture it is possible to produce water-in-oil emulsion ions with any !' optional amount of flavoring and coloring matter and a minimal amount of fat, j with the desired viscosity and with other physical properties for a given application. j

Figs 1 and 2 in the drawing are three-phase diagrams which respectively show how two and three variables in the mixture are changed to achieve a desired viscosity of a water-in-oil emulsion. The diagrams show the percentage amounts of water, sugar and oil component that can be used in a sugary emulsion. Bars designated A-T indicate the emulsifier concentrations used in specific mixtures, the height of each bar showing the total amount of emulsifier used, and each unit on a bar represents 2% emulsifier.

i'ig. 1 shows mixtures which are all prepared with 9.5$ (of the weight of the oil component) total emulsifying system, while Fig. 2 shows corresponding mixtures with varying amounts of emulsifying system. In the table below, the composition and viscosity of the different emulsions are listed at points A - I in fig. 1. The viscosity is measured using the well-known jMacMichael viscosities. (National Confectioners Association, jstandard method). This device measures the twist of a wire with a plumb bob immersed in a cup which is turned at a given speed and ! is filled with the mixture of which the viscosity is to be measured, as the sample is cooled to a specific temperature.

! It should be noted that even if the amount of emulsifying system is kept constant, widely different viscosities can be achieved. The high-viscosity emulsions indicated at points A and B are in themselves suitable as food or pleasure products, e.g. as cores in confectionery. Emulsions with viscosity 35 - 150 degrees MacMicha.el are : applicable for coating cakes, sugar toys and confectionery' and ! as sauces while emulsions with viscosities of 18 - 35 are a.n-'; turn over for coating with ice cream sticks and the like. Sta.vein in fig. 2 are indicated by letters from L to T, and de:i . the table below gives the composition and viscosity for different amounts of emulsifying system (4 - 12 #), indicated by the height of the bars L - T. It should be noted that all the mixtures according to table II are identical to the mixtures listed in table I with regard to total content of the oil component, water and sugar. The amount of emulsifier varies, however. 4 to 12% as shown in fig. 2. Mixture L is comparable to Mixture A (Table I) but is of the oil-in-water type. The viscosities in Table II are lower than for the corresponding mixtures in Table I, except for the mixtures N and Ij. It will be seen that significantly different viscosities can be achieved when different amounts of emulsifying system are used together with the same composition of the above-mentioned components. in ! In the mixtures A-T, hydrogenated palm kernel oil (Wiley m.p. 59°C) was used as fat, and 7.1% (based on the weight of the oil component) of an edible animal or vegetable oil was used. take car wax, such as beeswax. The emulsifiers used | for mixtures A-T, 1.31$ (calculated on the weight of the oil component) was acetylated, tartrated glyceryl monostearate (^Drewmulse" j j jA.T.M.S. Spee.) and 8.15 a/° (calculated on the weight of the oil component^ iglyceryl monooleate ( "Myverol 18-71E") which gives a ratio between hydrophilic and lipophilic emulsifiers of 13.85% to 86.15%. The above combination of emulsifiers gives a hydrophilicity-lipophilicity balance HLB (hydrophilic-lipophilic bnlance) in the range I from 3 to 6, which is accepted as the most advantageous for a water-in-oil emulsion (see Becher, Emulsions, Theory & Practice* ! |ACS Monograph 135, copyright 1957). i ! Water-in-oil emulsions are used which contain at least 1.8 % of water (indicated by bar AA in fig. 1) and at least 74 % of water (indicated by bar BB in fig. 1). Other percentage water content is reproduced by the various bars in Fig. 1 and 2, where the range !i for mixtures of suitable viscosity for the present water-in-oil emulsions is indicated by the area bounded by the lines X,Y and Z. i In the tables III and IV" below, the composition is indicated j for two satisfactory emulsions represented by the points AA <' jog BB on the line X, i.e. emulsions without sugar and with water content [corresponding respectively to the lower limit of 1.8 percent by weight and the upper limit of 74 percent by weight of the emulsion. The emulsion AA is also produced with a content of wax and emulsifying system corresponding to the lower limits for these, while the emulsion BB has a content of these components corresponding to the upper limit.

I The two emulsions AA and BB thus had a telling composition:

i See the percentage shares of the two main components in the nter-I Jjvgærravfæsrks the freemmusltsiljloninegr erog :of the optional sugar is as shown in the

In I01 component 4-.7 - 98.2% in water 1.8 - 74.0 £

sugar etc. 0 - 83.0 # j where "sugar etc." includes all water-soluble or water-releasable materials, if such are used, and the oil component

.includes fat, wax, emulsifying system and oil-soluble or oil-dispersible materials if such are used. The amount of emulsifying system can be as low as 1 56 (calculated on the weight of the oil component) in mixtures with a high fat content. Invert sugar, honey or corn syrup are used to reduce the degree of crystallization of sugar when cooling mixtures with a high sugar content. Snake and coloring agents can be added in any desired quantity to achieve the desired flavor or color strength. The offending substance can be any, any natural or synthetic flavor st ofl' As. aJta.eptabeit for use in food and recreational products. Son f genetic material must of course be used which is permitted for! use 1 nutritional and recreational means. This too can be natural or synthetic, and it can contain edible liquids, such as

glyceryl, propylene glycol and water. Both the flavoring and the coloring matter can be soluble or dispersible in either oil or water. both oil and water are suitable carriers for these. As mentioned above, it is not necessary to use sugar, and flavoring and coloring can be omitted or used as desired. Also^. other additives such as salt, preservatives or artificial sweeteners can be added as needed.

The use of natural, bleached or unbleached beeswax or other edible vegetable or animal wax in the range from 1 to 10% (of the weight of the oil component) enables the production of a greater range of water-in-oil emulsions than when the wax is omitted. The-; It has been shown that in order to achieve the desired emulsion stability, a suitable combination of hydrophilic emulsifying properties is required, provided e.g. of lecithin (of the oil/water type), and of lipophilic emulsifying properties provided e.g. of glyceryl monooleate. The emulsifier system gives the best results when it is dissolved in the fat phase. Combinations of lipophilic emulsifiers such as various glyceryl monooleates, certain glyceryl monostearates and propylene glycol esters, with hydrophilic emulsifiers such as acetylated, tartrated esters of monodiglycerides and polyoxyethylene-(20)-sorbitan monostearate and -oleate can be used. However, a lipophilic emulsifier alone can also be used, when this has the correct hydrophilicity/lipophilicity balance. The quantity used of a given emulsifier must be adapted to the purity. A number of examples of emulsifiers are given below, all of which are marketed products, and for which purity. |is specified.

The emulsification system used in the method according to the invention has been chosen to provide a hydrophilicity/lipophilicity balance (HLB) which has been shown to be the most effective in promoting adsorption at the interface between the two immiscible liquids, namely water and oil, to obtain a water-in-oil emulsion that will not invert or break when it is stored in a liquid or solid state or it is remelted after storage in a solid state. Such adsorption is a purely physical phenomenon as shown by the fact that the emulsions can be allowed to solidify and remelt repeatedly without any chemical change occurring. However, certain precautions are taken, as strong alkalis are avoided in the water and thinner materials which are known to inhibit or prevent the formation of water-in-the-emulsions or reduce their stability by chemical action on fields, emulsifiers or water phase. In .the..below, different emulsifiers are created with; indication, of. their most important characteristics. The emulsifiers are divided into hydrophilic and lipophilic emulsifiers and into thinners for use as a replacement or a certain proportion of the lipophilic emulsifiers.

! 1 (tested with hydrophilic emulsifier, "Myverol 1S-71E".) I

It will be seen that although the above tables each include compounds with the same chemical designation, the compounds are not the same, which is due to the different sources from which they originate and differences in the method of preparation. It will also be seen that the iodine number for compounds with the same designation varies widely. All the hydrophilic emulsifiers in Table V have a hydrophilicity/lipophilicity balance (HLB) of 7.8 or more, while the lipophilic emulsifiers in Table IV have a hydrophilicity/lipophilicity balance of 5.4 or less. With reference to Tables VI and VII, monoglycerides with an iodine value of 8 and higher or mixtures of such compounds can be used as primary lipophilic emulsifying agents in the preparation of water-in-oil emulsions, while all "saturated monoglycerides with an iodine value lower than 8 bere can be used as diluents and cannot be used as primary emulsifiers. It has been shown that up to 30% of the lipophilic water-in-oil-forming emulsifiers listed in Table VI can be replaced with the lipophilic diluents listed in Table VII (hereinafter referred to as the diluents for separate them from the primary emulsifiers) to reduce viscosity and to avoid a.t. the emulsion sticks in the mouth.

\ In the following, two mixtures with for-'

in different viscosities for different applications.

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The above concentrate was allowed to solidify and remelted repeatedly without any change in viscosity or physical properties. After dilution (8000 g concentrate to 4000 g oil) the viscosity was 27 - 30° MacMichael, as required for this emulsion for coating. of ice cream.- A number of ice cream sticks at 32°, stored at 20° and below, searched at short intervals over a period of 10 weeks.. They? no separation of oil took place, no decomposition of fat'., or spotting on the covering, and taste and aroma appeared; oh, intensify. After 10 weeks, the taste was good, the ice cream seemed "fresh", and there were no cracks in or other defects in the coating.

It has been shown that an impact mixer of the type for continuous operation or of the type for continuous operation can be used as long as the homogeneity during the addition of the water phase to the oil phase is maintained and the impact or whipping effect is sufficient to to ensure the known area for droplet crystallization from the dispersed water phase. It has been produced with good results up to o.a. 4,500 kg of water-in-oil emulsion with chocolate flavoring in lbpot of as little as 60 minutes in a continuous,. 6-stage mixer of the turbine type with a rotor of diameter 15 cm, which was driven at a speed of only 1200 rev/min. It has been found that the viscosity of a ferric emulsion can be reduced by simply adding additional amounts of melted fat or oil to the emulsion under relatively moderate stirring, the water-in-oil emulsion being maintained at or above the melting temperature. for the fat or oil.

In the following, an emulsion prepared according to the method according to the invention is compared with regard to stability with the same emulsion without wax addition. Each emulsion was prepared in the same way, namely as follows: j 1. The components of the oil phase are melted until a fully steady liquid state is obtained. This requires heating to 82 - 85°C for the waxy emulsion. After a complete melt has been achieved, the molten oil phase is placed in a container fitted with a heating jacket, through which heating jacket does it circulate? water from a hot water bath maintained at 49°C. The oil phase is stirred and cooled until it too holds 49°C.

2. The components of the aqueous phase are mixed (including by-products), and the temperature of the resulting mixture is raised to 49 |C. 3. When both the oil phase and the aqueous phase hold 49°C, an "Eppenbe.ch Homo-Mixer" mixer is added to the oil phase. The mixer is set to a rotation speed of 4000 revolutions per minute. minute. The aqueous phase is then added slowly over the course of approx. 20 I to I minutes. After all the liquid phase has been added, it is homogenized at 49°C and 10°C. aEnmduerlesn the joninen nstfirlemt - on ; .4000 revolutions per minute. 4. After the 30 minutes (total manufacturing time) of homogenization is completed, the homoblender is stopped and replaced with a turbine-type jet mixer operated at a speed of approximately 11'20 revolutions per minute. minute. The hot water bath is also replaced with a cold water bath which is used to cool the obtained emulsion to 32°C. , and the emulsion is placed in suitable test containers, while

the rest is placed in glass jars for later use.

The dyes and flavorings added to the two emulsions are also the same, and the concentrations used are shown below.

1 Rod å // 2 solution is prepared by dissolving 5 g of I Rod f 2 in 145 g of water! ' Rod jt 4 solution is prepared by dissolving 5 g of 1 Rod I 4 in 145 g of water

i i Felton Smakssto'ff (concentrated soluble imitation cherry no. 38)

The colorants are added to the aqueous phase before the emulsification is carried out, while the flavorings are added to the emulsion after homogenization.

yes! The tests that were carried out on these two emulsions to obtain comparative values are described below and likewise the experimental data for each test.

|1) Stability at room temperature; -?' y j After the emulsion has been cooled to 32°C, it is taken U'; _from. the homogenizing bell holder and placed in 1, 7

r jars which are then placed in a refrigerator where they are allowed to stand until the emulsion has solidified. They are then taken out and stored at room temperature. It is observed to what degree separation of phases takes place.

r [The'■."waxy emulsion: This emulsion does not separate (does not break). They are stable for several months when stored.

Emuls ion out n wax:

This emulsion is broken (the phases separate almost completely) because the emulsion has solidified. As soon as all stirring ceases during the production of this emulsion, phase separation begins immediately and is very easily visible. The separation is usually complete 15 minutes after stirring is opened, which means that when the jars are removed from the refrigerator, the broken fat phase lies above the colored water phase. 2) Melting of large kneaded emulsion;

u54t,5av °DC oen we nee"n n stbvog riksnsom. edrtbeidr" e. s eEmutfloter sr jdon aen t anaemnbuvrliennsgdjoeens se.n i een r somvn elvteetd , 49 ta-s the

Results: D a waxy emulsion; ;' .This emulsion melts without separation of the phases. • A certain amount of oil cream formation may occur, but any separated oil is easily resuspended by stirring lightly with a spatula. A smooth, liquid and stable emulsion is obtained. The emulsion without wax: This "emulsion" exhibits two phases which are slightly separated during the 3tbwerking. This is not really an "emulsion" after melting. Only with heavy rotation

.'' want; the two phases could be mixed again. If the conversion is stopped, however, the phases immediately separate again. The emulsion cannot be restored by light stirring with a spatula. in

Claims (1)

Method for the production of an edible hot-in-j oil emulsion which is suitable for coating or as a component rf.'in foodstuffs, in which method water, any flavoring and coloring additives and an oil component are mixed together. containing from 1.0 to 12.0 percent by weight or an emulsification system bej- consisting of from 0 to 75.0 weight percent of a non-ionic, hydrophilic emulsifying agent and from 100 to 25.0 weight percent of a non-ionic, lipophilic emulsifying agent, the total hydrophilic in tete/lipophilicity balance (HLB) of the emulsifying system the checkerboard is 3 - 6, j characterized by the fact that there as ollekomoonent na- ; is turned from 1.0 to 10 percent by weight, calculated on this, of a j melted animal or vegetable wax and such an amount of a j liquid or melted fat that the total amount of fat, emulsifier, wax and any oil-soluble or -dispersible ' smakss tof f is etc. is from 4.7 to 98.2 percent by weight calculate, on the "emulsion", that when a hydrophilic emulsifier is used, one with a fiLJJ of at least 7.8 is used, that a ; lipophilic. emulsifier with an HLB of hbyst 5.4 and an iodine number! of at least 8, as up to 30% by weight of the lipophilic emulsifier can be replaced with a lipophilic diluent with an eh HLB of at least 5.8 and an iodine number lower than 8, from 1.8 to 74.0% by weight of water, calculated on the emulsion, and which can contain up to 83% by weight of sugar and other water-soluble and water-dispersible flavorings etc., intended for the emulsion, are heated to the temperature of the mixture and added with sufficiently vigorous stirring so that the homogeneity of the mixture is maintained, and in that the mixture is mixed until the desired range of j droplet sizes of the aqueous phase of the emulsion is achieved.